Elisa D'Agati

The neurobiology of attention deficit/hyperactivity disorder

ADHD is a brain based disorder with structural and functional abnormalities in widespread but specific areas of the brain. The most significant and consistent structural imaging findings include smaller total brain volumes, and reduced volumes in the right frontal lobe, right parietal cortex, caudate nucleus, cerebellar hemispheres, and posterior-inferior lobules of the cerebellar vermis. ADHD involves hypofunction of catecholaminergic circuits, particularly those that project to the prefrontal cortex. A minimum of 18 genes have been reported to be associated with the disorder; among them the DRD4 7-repeat allele has been found associated with a thinner prefrontal and posterior parietal cortex. Epigenetic factors acting during critical periods of prenatal and postnatal development may interact with genetic determinants. Methylphenidate, as well as the catecholaminergic nonstimulant atomoxetine, are effective in improving ADHD symptoms.

The neurobiological basis of ADHD

Attention-Deficit/Hyperactivity Disorder is not a single pathophysiological entity and appears to have a complex etiology. There are multiple genetic and environmental risk factors with small individual effect that act in concert to create a spectrum of neurobiological liability. Structural imaging studies show that brains of children with Attention-Deficit/Hyperactivity Disorder are significantly smaller than unaffected controls. The prefrontal cortex, basal ganglia and cerebellum are differentially affected and evidence indicating reduced connectivity in white matter tracts in key brain areas is emerging. Genetic, pharmacological, imaging, and animal models highlight the important role of dopamine dysregulation in the neurobiology of Attention-Deficit/Hyperactivity Disorder. To date, stimulants are the most effective psychopharmacological treatments available for Attention-Deficit/Hyperactivity Disorder. Currently only immediate release methylphenidate and atomoxetine are approved for the treatment of ADHD in Italy. Drug treatment should always be part of a comprehensive plan that includes psychosocial, behavioural and educational advice and interventions.

Attention and executive functions profile in childhood absence epilepsy

Childhood absence epilepsy (CAE) has been associated with executive functions and attention deficits. To clarify the issue of neurocognitive impairments in CAE, we investigated whether specific executive functions and attention deficit patterns were present in a well-defined group of children with CAE who were taking valproic acid. Participants included 15 children with CAE and 15 healthy controls aged 8-15 years and matched for sex, age and IQ. We compared the performances of the two groups in the following neuropsychological domains: planning and problem solving (TOL), verbal fluency (FAS and CAT), verbal short-term memory (DSF), verbal working memory (DSB), visuospatial memory (Corsi Block Tapping Test) and sustained and divided attention (TMT-A and TMT-B). No differences were found between the two groups on measures of intellectual functioning, verbal short-term memory and visuospatial memory. By contrast, significant differences were found in total time of planning task, phonological and category fluency and sustained and divided attention. Future studies that systematically examine different aspects of attention and executive functions are needed to outline a clear and specific neuropsychological profile in CAE.

Overflow movements and white matter abnormalities in ADHD

Multiple motor abnormalities have been identified in some children with Attention Deficit/Hyperactivity Disorder (ADHD). These include persistence of overflow movements, impaired timing of motor responses and deficits in fine motor abilities. Motor overflow is defined as co-movement of body parts not specifically needed to efficiently complete a task. The presence of age-inappropriate overflow may reflect immaturity of the cortical systems involved in automatic motor inhibition. Theories on overflow movements consistently implicate impairments in white matter (WM) tracts, including the corpus callosum. WM connections might be altered selectively in brain networks and thus influence motor behaviours. We reviewed the scientific contributions on overflow movements and WM abnormalities in ADHD. They suggest that WM abnormalities in motor/premotor circuits, which are important for motor response inhibition, might be responsible for overflow movements in patients with ADHD.

Attention-Deficit Hyperactivity Disorder (ADHD) and Tuberous Sclerosis Complex

The neurobiological basis of attention-deficit hyperactivity disorder (ADHD) in tuberous sclerosis complex is still largely unknown. Cortical tubers may disrupt several brain networks that control different types of attention. Frontal lobe dysfunction due to seizures or epileptiform electroencephalographic discharges may perturb the development of brain systems that underpin attentional and hyperactive functions during a critical early stage of brain maturation. Comorbidity of attention-deficit hyperactivity disorder (ADHD) with mental retardation and autism spectrum disorders is frequent in children with tuberous sclerosis. Attention-deficit hyperactivity disorder (ADHD) may also reflect a direct effect of the abnormal genetic program. Treatment of children with tuberous sclerosis complex with combined symptoms of attention-deficit hyperactivity disorder (ADHD) and epilepsy may represent a challenge for clinicians, because antiepileptic therapy and drugs used to treat attention-deficit hyperactivity disorder (ADHD) may aggravate the clinical picture of each other.

Benign childhood epilepsy with centrotemporal spikes and the multicomponent model of attention: A matched control study

Although the high risk of cognitive impairments in benign childhood epilepsy with centrotemporal spikes (BCECTS) is now well established, there is no clear definition of a uniform neurocognitive profile. This study was based on a neuropsychological model of attention that assessed various components of attention in 21 children with BCECTS and 21 healthy children. All participants were tested with a computerized test battery using the multicomponent model of attention performance. In comparison with healthy participants, the children with BCECTS showed significant impairment in the measure of selectivity and in one measure of intensity of attention (arousal). Our results did not correlate with the electroclinical variables of age at onset of seizures and spike index on sleep EEGs. To the best of our knowledge, this is the first study in which the multicomponent model of attentional function has been used in children with BCECTS to provide a clearer neuropsychological profile of these patients.

Pathophysiology of NSS in ADHD

Attention deficit/hyperactivity disorder (ADHD) is the behavioural disorder most commonly diagnosed in childhood. In addition to the main symptoms of inattention, impulsiveness and hyperactivity, neurological soft signs (NSS) are often associated with ADHD. NSS are discrete motor and sensory disorders that cannot be linked to specific cerebral lesions. We review all the scientific contributions on NSS in ADHD. The conclusions support the presence of an alteration in the neural networks for motor control inhibition, at the base of the pathophysiology of NSS in children with ADHD, as well as a possible central role of dopamine in these neural circuits.

Attention impairment in childhood absence epilepsy: An impulsivity problem?

Although attention problems have often been described in children with childhood absence epilepsy (CAE), the use of different methodological approaches, neuropsychological tests, and heterogeneous experimental groups has prevented identification of the selective areas of attention deficit in this population. In this study, we investigated several components of attention in children with CAE using a unique computerized test battery for attention performance. Participants included 24 patients with CAE and 24 controls matched for age and sex. They were tested with a computerized test battery, which included the following tasks: selective attention, impulsivity, focused attention, divided attention, alertness, and vigilance. Compared with healthy controls, patients with CAE made more commission errors in the Go/No-Go task and more omission errors in the divided attention task. Childhood absence epilepsy patients also showed decreased reaction times in measures of selective attention and a great variability of reaction times in alertness and Go/No-Go tasks. Our findings suggest that patients with CAE were impaired in tonic and phasic alertness, divided attention, selective attention, and impulsivity.

Human endogenous retroviruses and ADHD

Abstract Objectives. Several lines of evidences suggest that human endogenous retroviruses (HERVs) are implicated in the development of many complex diseases with a multifactorial aetiology and a strong heritability, such as neurological and psychiatric diseases. Attention deficit hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that results from a complex interaction of environmental, biological and genetic factors. Our aim was to analyse the expression levels of three HERV families (HERV-H, K and W) in patients with ADHD. Methods. The expression of retroviral mRNAs from the three HERV families was evaluated in peripheral blood mononuclear cells (PBMCs) from 30 patients with ADHD and 30 healthy controls by quantitative RT-PCR. Results. The expression levels of HERV-H are significantly higher in patients with ADHD compared to healthy controls, while there are no differences in the expression levels of HERV-K and W. Conclusions. Since the ADHD aetiology is due to a complex interaction of environmental, biological and genetic factors, HERVs may represent one link among these factors and clinical phenotype of ADHD. A future confirmation of HERV-H overexpression in a larger number of ADHD patients will make possible to identify it as a new parameter for this clinical condition, also contributing to deepen the study on the role of HERVs in the neurodevelopment diseases.

Neurosteroids as Neuromodulators in the Treatment of Anxiety Disorders

Anxiety disorders are the most common psychiatric disorders. They are frequently treated with benzodiazepines, which are fast acting highly effective anxiolytic agents. However, their long-term use is impaired by tolerance development and abuse liability. In contrast, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment but have a slow onset of action. Neurosteroids are powerful allosteric modulators of GABAA and glutamate receptors. However, they also modulate sigma receptors and they are modulated themselves by SSRIs. Both pre-clinical and clinical studies have shown that neurosteroid homeostasis is altered in depression and anxiety disorders and antidepressants may act in part through restoring neurosteroid disbalance. Moreover, novel drugs interfering with neurosteroidogenesis such as ligands of the translocator protein (18 kDa) may represent an attractive pharmacological option for novel anxiolytics which lack the unwarranted side effects of benzodiazepines. Thus, neurosteroids are important endogenous neuromodulators for the physiology and pathophysiology of anxiety and they may constitute a novel therapeutic approach in the treatment of these disorders.